Pigment Cell & Melanoma Research最新文献

Intra-tumoral heterogeneity poses a major challenge to treating and managing cancer patients. A characteristic feature of melanoma is its composition of cancer cells with typically heterogeneous content of melanin pigment, the production of which is a hallmark of normal melanocytic differentiation but of poorly understood consequence in melanoma cells, as prospective assessment of pigment heterogeneity in melanoma cells has been experimentally challenging. Here, we describe a novel flow cytometric method for high purity separation of viable melanoma cells based on their melanin content, exploiting the light scattering properties of melanin. By fluorescence-activated cell sorting, we show that cells with low-pigment content (LPCs) in melanoma cell lines and patient tumors are usually far more abundant than high-pigment cells (HPCs) and have substantially increased potentials for colony formation in vitro and tumor formation in vivo. In RNAseq analysis, HPCs showed P53 activation and perturbed cell cycling, whereas LPCs displayed upregulation of MYC-associated transcription and activated ribosome biogenesis. In proof-of-concept studies, the latter was targeted by topoisomerase 2 beta targeting with CX-5461, which induced senescent HPC phenotypes and irreversible loss of clonogenic activity. These data indicate an ‘inverted pyramid’ hierarchical model of melanoma cell propagation wherein abundant LPCs frequently renew their own malignant potential to propagate disease but also infrequently generate HPCs that spontaneously lose this ability in a manner that might be exploited as an anti-melanoma strategy.

The melanocortin 1 receptor (MC1R) is well-established as a pivotal regulator of pigmentation in various species. Despite a wealth of research focused on mammals and fish, the role of Mc1r in amphibians has remained largely unexplored. This study was designed to elucidate the contribution of Mc1r in Xenopus tropicalis. Our results reveal that targeted ablation of mc1r in Xenopus tropicalis led to a significant reduction in dorsal skin pigmentation, while simultaneously accelerating the onset of melanophore pigmentation in the ventral region. This dual effect resulted in a perturbation of the canonical countershading pattern. Additionally, knockout of mc1r disrupted the expression of multiple genes primarily associated with pigmentation. Collectively, these findings underscore the critical role of MC1R in the regulation of pigmentation and the development of countershading in amphibians, contributing to the growing body of literature on the evolution and function of MC1R across vertebrate species.

Dyschromatosis universalis hereditaria (DUH) is a rare genodermatosis characterized by asymptomatic hyper- and hypopigmented macules appearing in infancy and persisting for life. Although mutations in ABCB6 account for many DUH cases, recently, the SAM and SH3 domain-containing 1 (SASH1) gene has emerged as a key player in DUH. Additionally, SASH1 mutations have been associated with the pure-lentiginous phenotype of familial pigmentation. In this review of literature, we found 22 different SASH1 mutations, most inherited in an autosomal dominant manner. These variants cause distinct phenotypes, including DUH, lentiginosis, and rarely, an autosomal recessive syndromic form with alopecia, palmoplantar keratoderma, and increased risk of malignancies. Functional studies have revealed that SASH1 acts as both a tumor suppressor and a pro-melanogenic factor. It modulates key pathways such as p53–POMC–α-MSH–MC1R–MITF and Gαs-SASH1–IQGAP1–E-cadherin pathways, affecting melanosome production, transport, and melanocyte migration. This unique dual role of SASH1 highlights its importance in melanocyte homeostasis and UV-induced pigmentation. Understanding the role of SASH1 in regulating pigmentation can help foster novel therapeutic approaches for these genodermatoses and related pigmentary anomalies, ultimately improving patient care and outcomes.

Vitiligo is an acquired depigmentation disorder characterized by the loss of melanocytes. The specific etiology of vitiligo is not fully understood, but it is thought to result from a complex interplay of factors, including autoimmune responses, intrinsic melanocyte dysfunction, genetic susceptibility, oxidative stress, and neurogenic imbalances. The disfiguring nature of vitiligo significantly impacts the mental and physical health of patients, and psychological stress can further induce and exacerbate vitiligo. Recent research has underscored the potential mediating roles of the hypothalamic–pituitary–adrenal axis, hormones, and neuropeptides in the pathogenesis of vitiligo. Furthermore, individuals with vitiligo have been shown to have a notably higher prevalence of diabetes mellitus and metabolic syndrome compared to the general population. This evidence suggests that vitiligo is not merely a cosmetic issue confined to the skin but also a systemic disease with broader health implications. This review aims to explore the potential roles and mechanisms of neuroendocrine factors in the pathogenesis of vitiligo, shedding light on the multifaceted nature of this condition and its systemic associations.

Circulating tumor cells (CTCs) can provide non-invasive insight into how a cancer patient responds to therapy. Their role in disease monitoring of advanced melanoma patients treated with immune checkpoint inhibitors (ICI) is unknown. CTC protein expression of human leukocyte antigen class-I (HLA I) and programmed death ligand-1 (PD-L1) may give insight into how a patient's disease evolves over the course of treatment. In our study, we utilize microfluidic Exclusion-based Sample Preparation (ESP) technology to isolate and characterize CTCs from patients with advanced-stage melanoma. CTC samples from melanoma patients are collected, captured, and stained. A range of 2 to 35 CTCs is observed in a cohort of 16 samples from 10 advanced-stage melanoma patients treated with ICI therapy. Single-cell protein expression data is generated from image cytometry analysis and used to calculate mean HLA I and PD-L1 expression. Using our ESP capture approach, we successfully detect phenotypic and numerical heterogeneity in CTCs from melanoma patients. Our assay shows sufficient capture sensitivity and promising prognostic and predictive information, as we illustrate in our case example. A greater clinical sample size will be necessary to confirm the diagnostic sensitivity and specificity of the assay in predicting clinical outcomes for patients with advanced-stage melanoma.

The unique pharmacokinetics of BRAF and MEK inhibitors make patients vulnerable to drug–drug interactions (DDIs), which may compromise treatment efficacy in metastatic melanoma. This study evaluates the impact of DDIs on clinical outcomes in patients with metastatic melanoma treated with BRAF/MEK inhibitors. This multicenter, observational, retrospective study assessed DDIs using the Drug-PIN software. Associations between the Drug-PIN continuous score, Drug-PIN light, and treatment outscomes were analyzed along with the specific drugs involved in the DDIs. A total of 177 patients with BRAF-mutant metastatic melanoma undergoing BRAF/MEK inhibitor therapy were included. Of these, 94 patients (55.9%) were exposed to complex drug regimens related to comorbidities, supportive care, and symptom management. A significant change in Drug-PIN scores was observed before and after therapy initiation. Patients with low-grade DDIs demonstrated significantly longer median overall survival (OS) and progression-free survival (PFS) compared to those with high-grade DDIs (log-rank p = 0.0045 and p = 0.012, respectively); this observation was further validated by multiple regression analysis. By combining clinical and DDI data, we identified four patient subgroups with distinct prognoses, showing statistically significant differences in OS and PFS (log-rank p < 0.0001). The subgroup with the highest clinical risk and high DDI had markedly poorer outcomes (HR 2.87, 95% CI [1.7–4.8], p < 0.001). The drugs involved in high-level pharmacological interactions were analyzed. DDIs significantly contribute to poorer OS and PFS outcomes, independent of other clinical risk factors. Optimizing pharmacological regimens to minimize DDIs should be prioritized to enhance treatment efficacy in oncology. Prospective clinical trials are warranted to further validate the advantages of individualized, preemptive therapy optimization.

Acral lentiginous melanoma (ALM) is a rare and insufficiently understood subtype of melanoma lacking in effective treatment options. Recent work has demonstrated that the response of ALM to immune checkpoint blockade is inferior to that of cutaneous melanoma (CM). Here we performed bulk genomic and transcriptomic sequencing of tumor tissue from 28 ALM and 5692 CM cases. Similar to prior studies, ALM was associated with a significantly lower incidence of point mutations, including in the TERT promoter and BRAF, but increased numbers of gene amplifications, notably of CCND1, HMGA2, and MDM2. Reactome pathway analysis revealed enhancement of keratinization and PI3K/AKT signaling pathways. Overall immunogenicity was decreased in ALM, which possessed lower IFNγ (p < 0.001) and T-cell inflammatory (p = 0.03) pathway scores than CM. Despite higher computationally inferred levels of myeloid dendritic cells (p = 0.006), neoantigen load independent of predicted HLA binding affinity was lower (p < 0.01) in ALM versus CM. Assessment of classical and nonclassical HLA mRNA levels revealed upregulation of HLA-G, suggesting alternative ALM immune evasion pathways in the setting of lower PD-L1 expression (p = 0.005). Additional research is needed to better understand and therapeutically target signaling networks in the ALM tumor microenvironment.

Natural selection has rarely promoted the evolution of colour polymorphism in wild mammals. However, it is more common in domestic mammals due to artificial selection. For this reason, domestication could provide valuable insights into the mechanisms underlying the evolution of colour diversity. This raises the question of whether the associations between coat colour and other phenotypes in domestic animals are similar to those in free-living animals. Our literature review of cows, goats and sheep suggests that these associations can differ not only between species but also within and between breeds. This pattern holds for all the traits that we considered: morphology, behaviour, physiology, reproduction, milk production and parasitism. The only consistent association we found in the literature was the attraction of flies towards dark-coloured cows. The relationships between same colour morph, cortisol and thermoregulation varied across environments, suggesting a possible condition-dependent expression of multiple traits. We conclude that artificial selection may lead to a different integration of multiple phenotypes compared to animals living in the wild. Therefore, colour variation may not always serve the same functional roles in domestic animals as it does in wild ones.